Different functional domains measured by cocaine self-administration
under the progressive-ratio and punishment schedules in male
Received: 18 May 2017 /Accepted: 29 November 2017 /Published online: 6 December 2017
Springer-Verlag GmbH Germany, part of Springer Nature 2017
Background Current diagnosis of drug addiction like other mental disorders is based on clinical symptoms not on neural
pathophysiology and consequently, does not provide useful information on the underlying pathophysiology and may impede
the efforts to identify the underlying mechanisms. Identifying the functional deficits that are relevant to addiction and can be
traced to the neural systems will greatly facilitate our understanding of the heterogeneity of the condition and improve future
diagnosis and treatment. Cocaine addiction is characterized by the continued use despite the dire consequences, and the deficit in
inhibitory control may play a key role in this process. This study aimed to develop a paradigm to measure the punishment-
induced inhibitory regulation of reward-seeking behavior.
Methods Rats were first trained to self-administer sucrose pellets under a chained schedule and then the breaking points (BPs)
under the progressive-ratio schedule, and the intensity-response effects of footshock punishment on sucrose SA were measured.
Subsequently, the rats went on to self-administer intravenous cocaine, and the BPs and the punishment intensity-response effects
were similarly determined.
Results The areas under the punishment intensity-response curves (AUCs) were calculated and used as an indicator of the
sensitivity of the inhibitory system. The BPs for cocaine were not correlated with the AUCs. Furthermore, the change in the
BPs for cocaine induced by changing cocaine dose did not predict the change in the AUCs.
Conclusion The intensity-response effects of punishment can be used to measure the function or sensitivity of the inhibitory
system independent of the motivational state.
Research domain criteria
Drug addiction is a chronic, relapsing, mental disorder and
characterized by the compulsive drug-seeking and drug-
taking behaviors. Its diagnosis is largely based on the patho-
logical pattern of drug use (American Psychiatric Association
2013). One prominent issue with such an approach is the
heterogeneity of the diagnosis. Patients with the same diagno-
sis could present different combinations of the symptoms.
Such a heterogeneity poses a significant problem for treatment
because the heterogeneous patients unlikely respond to the
same treatment equally well. Incorporation of the
neuroscience-based criteria indicating the impairments of the
neural systems or functional domains may significantly im-
prove the diagnosis (Cuthbert and Insel 2010; Insel et al.
2010). The NIMH has proposed Research Domain Criteria
(RDoC) that presently have identified five brain systems or
functional domains germane to mental disorders: negative va-
lence system, positive valence system, cognitive systems, sys-
tems for social processes, and arousal/regulatory systems
(Insel et al. 2010). Heeding such a shift, the National
Institute of Alcohol Abuse and Alcoholism (NIAAA) has pro-
posed Alcohol Addiction RDoC (AARDoC) and temporarily
proposed six domains: reward, stress, affect, incentive sa-
lience, executive function, and social processes relevant to
alcohol addiction (Litten et al. 2015). Encouraged by these
Drs. Martini and Datta equally contributed to this paper.
* WenLin Sun
Department of Pharmacology, University of Tennessee Health
Science Center, 71 S. Manassas, Memphis, TN 38103, USA
Psychopharmacology (2018) 235:897–907